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Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice


Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms1,2. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD3,4. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component5,6,7,8. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5−/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.

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Figure 1: Targeted inactivation of Slitrk5 in mice and its expression pattern in the mouse brain.
Figure 2: Facial lesions, OCD-like behavior and its alleviation with fluoxetine treatment in Slitrk5-knockout mice.
Figure 3: Metabolic changes in the cortex and anatomical defects in the striatum of Slitrk5−/− mice.
Figure 4: Deficiency in corticostriatal transmission in Slitrk5−/− mice is mediated by changes in glutamate receptor composition.


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We thank M. Flint Beal for providing expertise on behavioral experiments. We thank G. Thurston for critical comments and suggestions. PSD95-cherry was a kind gift from R.H. Edwards (University of California–San Francisco). We acknowledge support from US National Institutes of Health grants MH079513 (F.S.L.) and NS052819 (F.S.L.), HL66592 (S.R.), HL097797 (S.R.) and AI080309 (S.R.), Burroughs Wellcome Foundation (F.S.L.), International Mental Health Research Organization (F.S.L.), the Sackler Institute (K.G.B., F.S.L.), DeWitt-Wallace Fund of the New York Community Trust (F.S.L.), Pritzker Consortium (F.S.L.), National Alliance for Research on Schizophrenia and Depression (S.V.S.), Mildred-Scheel-Stiftung, Deutsche Krebshilfe (T.M.), Gulbenkian PhD Programe in Biomedicine (C.C.P.), Fundacao para Ciencia e Tecnologia (C.C.P.), Howard Hughes Medical Institute (S.R.), Ansary Stem Cell Institute (S.R.), Anbinder and Newmans Own Foundations (S.R.), Qatar National Priorities Research Program (S.R.), Empire State Stem Cell Board (S.R.) and the New York State Department of Health grant NYS C024180 (S.R.).

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Authors and Affiliations



S.V.S. conceived of and designed the study, performed experiments, analyzed data and wrote the manuscript; A.H., D.J, C.C.P. and K.G.B. designed and performed experiments, analyzed data and assisted in writing the manuscript; T.M., E.S., J.S.K., M.B. and I.D. performed experiments and analyzed data; A.J.M., D.M.V., N.W.G. and G.D.Y. designed and generated the Slitrk5−/− mice; I.N. designed, performed and analyzed electrophysiology experiments; F.S.L. and S.R. conceived of and designed the study and wrote the manuscript.

Corresponding authors

Correspondence to Francis S Lee or Shahin Rafii.

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The authors declare no competing financial interests.

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Shmelkov, S., Hormigo, A., Jing, D. et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice. Nat Med 16, 598–602 (2010).

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